Photoclick and Release: Co‐activation of Carbon Monoxide and a Fluorescent Self‐reporter, COS or Sulfonamide with Fast Kinetics

Abstract

Bioorthogonal prodrugs with both fast reaction kinetics and multiple outputs are highly desirable but are only found sporadically. Herein, we report a novel photoclick-and-release strategy for the co-activation of carbon monoxide and a selfreporter, carbonyl sulfide, or sulfonamide with fast reaction kinetics (k: 1.4-22.6 M À 1 s À 1 ). Such a photoclick-and-release strategy was successfully applied in live cells to deliver carbon monoxide and a fluorescent self-reporter, both of which exhibited pronounced antiproliferative activity against 4T1 cancer cells. It is conceivable that this photoclick-and-release strategy could find applications in other fields, in which a controlled bond cleavage is preferred.

Bioorthogonal Bond Cleavage Chemistry for On-demand Prodrug Activation: Opportunities and Challenges

“…Another feasible strategy to defy the trade-offs between reactivity and stability is to cage the highly reactive click reagent in a form that is very stable under physiological conditions and possesses no or sluggish reactivity toward its partner, while it can be readily transformed into the highly reactive trigger reagent for prodrug activation in the presence of a stimulus. A unique example, in this case, is the “photoclick and release” strategy, which can be employed to address the stability issues of the reagents (i.e., tetrazines). − In addition to photoirradiation, other endogenous metabolites or enzymes can also be potentially leveraged to achieve the transformation by caging the dihydrotetrazine with corresponding responsive groups. Moreover, this strategy can not only address the stability issues of reagents but also specifically confine the “click and release” event in a well-defined space, thus eliminating off-target effects.…”

“…Another built-in advantage of this photoclick and release strategy is that multiple outputs were achieved with one single click reaction, which may prove to be invaluable for combinational therapy. 130 To address the stability issues of tetrazines as well as to enhance the temporospatial resolution of the click and release event, photoresponsive tetrazine precursor 140 was elegantly designed. Such a precursor lost its reactivity toward dienophiles (i.e., TCO), and presented substantially enhanced stability under physiological conditions (less than 1% of decomposition was noticed after 24 h incubation in PBS, while the majority of tetrazine was decomposed under the same conditions).…”

Bioorthogonally Assisted Phototherapy: Recent Advances and Prospects

“…Further to this, in 2023, Liu et al. described a cyclopropenone‐caged strained alkyne precursor which was unmasked by UV light to react with dienones with an accompanied release of carbon‐monoxide followed by cancer cell cytotoxicity [85] …”

A Bioorthogonal Decaging Chemistry of N-Oxide and Silylborane for Prodrug Activation both In Vitro and In Vivo

“…In contrast, the bioorthogonal prodrug strategy can mitigate the issues of heterogeneity because the “levels” of the stimulus (an exogenously administrated clickable reagent) can be precisely controlled. During the past decade, tremendous progress has been witnessed in this field with a myriad of bioorthogonal prodrugs being developed. − Among these strategies, the one using the click reaction between tetrazine and trans -cyclooctene represents one of the most effective in achieving specific drug activation in cells and in mice due to its fast click kinetics and high efficiency in prodrug activation. − Encouragingly, one such bioorthogonal prodrug from this category has successfully entered Phase II clinical trials (SQ3370-001; NCT04106492), and the data from Phase I trial has well-established SQ3370-001’s safety and localized activation at the tumor sites in human …”